Used in the treatment of Human Immuno Deficiency Virus (HIV) infection, prevention of mother to child transmission of the HIV virus and occupational post exposure prophylaxis.

HIV Life Cycle

In order for viruses to reproduce, they must infect a cell. HIV's genes are carried in two strands of RNA, while the genetic material of human cells is found in DNA. In order for the virus to infect the cell, a viral enzyme called reverse transcriptase makes a DNA copy of the virus's RNA in a process called "reverse transcription". Without reverse transcriptase, the viral genome cannot become incorporated into the host cell, and cannot reproduce.

Once the viral RNA has been reverse-transcribed into a strand of DNA, the DNA can then be inserted into the DNA of the lymphocyte. The viral enzyme called "integrase" facilitates incorporation of the viral DNA into the host cells DNA. This new DNA is called "proviral DNA”.

Activation of the host cells results in the transcription of viral DNA into messenger RNA (mRNA), which is then translated into viral proteins. The new viral RNA forms the genetic material of the next generation of viruses.

The polypeptide sequence which mRNA produces is assembled in a long chain that includes several individual proteins (reverse transcriptase, protease, integrase). Before these enzymes become functional, they must be cut from the longer polypeptide chain. Viral protease cuts the long chain into its individual enzyme components and processes other HIV proteins into their functional forms that facilitate the production of new viruses.

Reverse Transcriptase Inhibitors

Reverse transcriptase inhibitors are divided into two classes-nucleoside analogues and non-nucleoside reverse tran-scriptase inhibitors based on their structure and how they inhibit reverse transcriptase.

Nucleoside analogues, the first class of HIV drugs to be developed, work by incorporating themselves into the virus’ DNA, making the DNA incomplete and therefore unable to create a new virus. Non-nucleoside inhibitors work at the same stage as nucleoside analogues, but attach themselves to reverse transcriptase and prevent the enzyme from converting RNA to DNA.

Nucleoside Analogues

• abacavir (Ziagen®)
• AZT, ZDV, zidovudine (Retrovir®)
• lamivudine (3TC ®)
• zidovudine/lamivudine (Combivir®)
• d4T stavudine (Zerit®)
• ddI didanosine (Videx®)

Non-nucleoside inhibitors

• nevirapine (Viramune®)
• delavirdine (Rescriptor®)
• efavirenz (Stocrin™)

Protease Inhibitors

HIV protease is required for HIV replication and formation of mature, infectious viral particles. This processing function is inhibited by protease inhibitors, resulting in production of noninfectious viral particles:

• ritonavir (Norvir®)
• indinavir (Crixivan®)
• nelfinavir (Viracept®)

FIRST-LINE THERAPY

Regimens should be chosen on the basis of their potency, tolerability, reported adverse effects and potential reactions with other drugs, convenience, and likelihood of patient compliance. Also to be considered are possible alternative treatments if the first regimen fails.

The initial regimen should include two nucleoside reverse transcriptase inhibitors (nRTIs) and one or two protease inhibitors (PIs) or two nRTIs and a nonnucleoside reverse transcriptase inhibitor Combinations of agents from all three classes, considered an aggressive regimen, may be appropriate for patients at high, short-term risk of disease progression.

Drug Interactions

Protease inhibitors and non-nucleoside reverse transcriptase inhibitors are metabolized by the CP450 system and cause many drug interactions, which include:

• Imidazole antifundals
• Some macrolide antibiotics e.g.
  • clarithromycin
  • Cimetidine
  • ‘Statin’ antilipemics
  • Phenytoin, carbamazepine